Melanin concentrating hormone, or MCH, is a cyclic 19 amino acid neuropeptide that functions as a regulator of food intake and energy balance. MCH is produced in the hypothalamus of many vertebrate species, including humans, and serves as a neurotransmitter in the lateral and posterior hypothalamus. Both of these regions have been associated with behaviors such as eating, drinking, aggression and sexual behavior. MCH is also produced at various peripheral sites, including the gastrointestinal tract and testis.
The postulated role of MCH in feeding behavior and body weight has been confirmed by the finding that I.C.V. injection of MCH into the lateral ventricle of the hypothalamus increases caloric consumption in rats over similarly treated control animals. Furthermore, rats having the ob/ob genotype exhibit a 50-80% increase in MCH mRNA expression as compared to leaner ob/+ genotype mice. MCH knockout mice are leaner than their MCH-producing siblings due to hypophagia and an increased metabolic rate.
MCH activity is mediated via binding to specific receptors. The MCH type 1 receptor (MCHR1) is a 353 amino acid, 7-transmembrane, alpha-helical, G-coupled protein receptor, first reported by Lakaye, et al. (BBA (1998) 1401:216-220). MCHR1 has also been known as SLC-1. Immunohistochemistry studies of rat brain sections indicate that the MCHR1 receptor is widely expressed in the brain. MCHR1 receptor expression has been found in the olfactory tubercle, cerebral cortex, substantia nigra, basal forebrain CA1, CA2, and CA3 field of the hippocampus, amygdala, and in nuclei in the hypothalamus, thalamus, midbrain and hindbrain. Strong signals have been observed in the ventromedial and dorsomedial nuclei of the hypothalamus, two areas of the brain known to be involved in feeding behavior. Upon binding MCH, MCHR1 receptors expressed in HEK 293 cell mediate a dose dependent release of intracellular calcium. Cells expressing MCH receptors have also been shown to exhibit a pertussis toxin sensitive dose-dependent inhibition of forskolin-levated cyclic AMP, indicating that the receptor couples to a Gi/o G-protein alpha subunit.
Recently, a second MCH receptor (MCHR2) has been identified (An et al., Proc. Natl. Acad. Sci. USA (2001) 98:7576-7581; Sailer et al., Proc. Natl. Acad. Sci. USA (2001) 98:7564-7569; Hill et al., J. Biol. Chem. (2001) 276:20125-20129; Mori et al., Biochem. Biophys. Res. Commun. (2001) 283:1013-1018). MCHR2 has an overall amino acid identity of more than 30% with MCHR1, and is detected specifically in most regions of the brain, with an expression pattern similar to that of MCHR1.
Because MCH is an important regulator of food intake and energy balance, agents capable of modulating MCH receptor activity, especially MCHR1, are highly desirable for the treatment of obesity, eating disorders (e.g., bulimia and anorexia), sexual disorders (e.g., anorgasmic or psychogenic impotence) and metabolic disorders, such as diabetes. Small molecule, non-peptide antagonists of MCH receptors would be of particular value for such therapies. The present invention fulfills this need, and provides further related advantages.